The application of allogeneic bone marrow transplantation (BMT) has been impeded by the development of its severe complication, acute graft-versus-host disease (GVHD). Alloreactive donor T cells are critical for causing GVHD. Naturally occurring thymic derived donor CD4+CD25+Foxp3+ regulatory T cells (Tregs) suppress experimental GVHD. However the mechanism of GVHD suppression by the donor Tregs is not well understood. Several recent observations have also brought in a renewed focus on the role of host professional antigen presenting cells (APCs) in the induction and maintenance of GVHD. But the role of APCs in modulating the responses of Tregs after allogeneic BMT is not known. The central premise of this proposal is that host APCs are critical for the induction, function and regulation of Treg mediated suppression of GVHD. In this proposal we will build on our exciting preliminary observations that demonstrate a requirement of APCs in Treg mediated reduction of GVHD. The specific aims of this proposal are: Specific Aim 1: To determine the requirement of APCs in induction of donor type natural CD4+CD25+Foxp3+ regulatory T cells (Tregs) mediated regulation of GVHD. Specific Aim 2: To analyze the role of APCs in modulating the function of Tregs as determined by the suppression of GVHD. Specific Aim 3: To elucidate the critical cellular and molecular mechanisms for the positive and negative regulation of Treg mediated reduction in GVHD by the APCs. Allogeneic bone marrow transplantation (BMT) is a curative therapy for a number of blood diseases. However, the application of this effective therapy has been impeded by the development of its most severe complication, graft-versus-host disease (GVHD). Our proposal aims to understand the underlying mechanisms of interaction between various immune cells that are critical for GVHD. If successful, this could reduce GVHD and make allogeneic BMT safer.